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Sphingolipids and Myelin Structure

Sphingolipids and Myelin Structure. Outlines. Objectives. Background. Key principles. Take home messages. Objectives. By the end of this lecture, the students should be able to:

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Sphingolipids and Myelin Structure

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  1. Sphingolipids and Myelin Structure

  2. Outlines • Objectives. • Background. • Key principles. • Take home messages.

  3. Objectives By the end of this lecture, the students should be able to: • Recognize the Sphingolipids class of lipids as regard their chemical structure, tissue distribution and functions. • Be familiar with the biochemical structure and function of myelin. • Learn the basics of biosynthesis of sphingolipids. • Be introduced to Sphingolipidoses.

  4. BACKGROUND • There are two classes of phospholipids based on the backbone: • Glycerol (from glucose). • Sphingosine (from serine and palmitate).

  5. BACKGROUND (Cont’d…) • Essential component of membranes. • Abundant in nervous tissue. • Also exist extra-nervous tissue: • e.g. Receptors for: • Cholera toxins • Diphtheria toxins • Viruses.

  6. BACKGROUND (Cont’d…) • Regulation of growth and development. • Very antigenic: • Blood group antigen • Embryonic antigen • Tumor antigen • Cell transformation.

  7. Key Principles • Chemical structure of Sphingolipids. • Types: • Glycosphingolipids (Glycolipids). • Sphingophospholipids, e.g. Sphingomyelin. • Myelin structure and function. • Sphingolipidoses.

  8. Sphingolipids:Structure and types

  9. Sphingosine Long chain, unsaturated amino alcohol CH3 (CH2)12 CH CH CH CH CH2OH OH NH2

  10. Ceramide Ceramide = Sphingosine + Fatty acid Long chain fatty acid CH3 (CH2)12 CH CH CH CH CH2OH OH NH C (CH2)n CH3 O • Ceramide play a key role in maintaining the skin’s water-permeability barrier. • Decreased ceramide levels are associated with a number of skin diseases.

  11. Sphingomyelin Sphingomyelin = Ceramide + Phosphorylcholine Long chain fatty acid CH3 (CH2)12 CH CH CH CH CH2O Phosphorylcholine OH NH C (CH2)n CH3 O • Sphingomyelin is the only significant sphingolipid in humans

  12. Cerebrosides Cerebrosides = Ceramide + Monosaccharides e.g. Galactocerebroside.

  13. Gangliosides Gangliosides = Ceramide oligosaccharides + NANA e.g. GM2. • For GM2: G=ganglioside; M=mono molecule of NANA; 2=the monomeric sequence of the carbohydrate attached to the ceramide (NANA)

  14. Sphingolipids’ Synthesis

  15. Myelin Structure Myelinis a specialized cell membrane that ensheathes an axon to form a myelinated nerve fiber. Myelinis produced by: Schwann cells:Peripheral nerves. Oligodendrocytes: CNS. Myelincomposition: Lipids (80%):Main component:Cerebrosides Other component: Sphingomyelin Proteins (20%): e.g. Myelin basic protein

  16. Myelin Structure Fatty acid of Sphingomyelin: Myelin sheath: Very long chain fatty acids Lignoceric 24:0 Nervonic 24:1(15)

  17. Myelin Structure and function Myelin sheath insulates the nerve axon to avoid signal leakage and greatly speeds up the transmission of impulses along axons. Multiple sclerosis: Neuro-degenerative, auto-immune disease. Breakdown of myelin sheath (demyelination). Defective transmission of nerve impulses. Direction of nerve impulse

  18. SphingolipidosEs • A partial or total missing of a specific lysosomal acid hydrolase leads to accumulation of a sphingolipid. • Lysosomal lipid storage diseases caused by these deficiencies are called sphingolipidoses.

  19. SphingolipidosEs (Cont’d…) • Synthesis (Normal); Degradation (Defective). • Substrate accumulates in organs.. • Progressive, early death. • Phenotypic and genotypic variability. • Autosomal recessive (mostly). • Rare, Except in Ashkenazi Jewish. • Usually only a single sphingolipid accumulates in the involved organs in each disease

  20. SphingolipidosEs (Cont’d…) • Diagnosis: • Measure enzyme activity: • Cultured fibroblasts or peripheral leukocytes. • Cultured amniocytes or chorionic villi (prenatal). • Histologic examination. • DNA analysis. • Treatment: e.g. for Gaucher disease: • Replacement Therapy (e.g. recombinant human enzyme). • Bone marrow transplantation.

  21. SphingolipidosEs

  22. Niemann-pick disease

  23. Gaucher disease

  24. Take home messages • Sphingolipids are complex lipids that includes sphingo-phospholipids and glycolipids. • Ceramide is the precursor of all sphingolipids. • Sphingolipids are present mainly in nerve tissue, but they are also found extra-neural. • Myelin sheath insulates the nerve axon to avoid signal leakage and speed up impulse transmission. • Sphingolipidoses are rare genetic diseases due to defective degeneration of sphingolipids.

  25. Reference Lippincott Illustrated Review of Biochemistry, 6th edition, 2014, Unit 3, Chapter 17, Pages 201-218.

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